REGENERATE: Final Results for Obeticholic Acid for Pre-Cirrhotic Fibrosis Due to NASH

Arun Sanyal, MD

Credit: Virginia Commonwealth University

Final end-of-study results from the phase 3 REGENERATE study of obeticholic acid (OCA) for the treatment of pre-cirrhotic fibrosis due to nonalcoholic steatohepatitis (NASH) highlight the farnesoid X receptor agonist’s trend in benefit for clinical outcomes.¹

Data presented at Digestive Disease Week (DDW) 2024 in Washington, DC, showed histological progression to cirrhosis was reduced in patients receiving OCA 25 mg and ≥1 stage improvement in fibrosis was observed in patients taking OCA 10 mg, additionally highlighting no new safety concerns with >2 years of additional exposure.¹

Although there was hope that OCA would become the first US Food and Drug Administration (FDA)-approved therapeutic for NASH, a Gastrointestinal Drugs Advisory Committee meeting on May 29, 2023, yielded a pair of negative votes related to its New Drug Application (NDA) with more than two-thirds of the committee voting against the risk-benefit profile of the agent and 15 of the 16 committee members voting to defer approval until further clinical outcomes data was submitted and reviewed. Nearly a month later, Intercept Pharmaceuticals received a Complete Response Letter (CRL) requiring successful completion of the long-term outcomes phase of the REGENERATE study for resubmission of an NDA.^2,3

Instead, Intercept opted to discontinue all NASH-related investments and restructure the company’s operations to focus on rare and serious liver diseases.3 Thus, REGERATE was prematurely discontinued in September 2023. Final end-of-study results for the multicenter, randomized, double-blind, placebo-controlled study were presented at DDW by Arun Sanyal, director of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health at Virginia Commonwealth University.¹

Patients with biopsy-confirmed fibrosis (F2–F3) were randomly assigned in a 1:1:1 ratio to receive placebo, OCA 10 mg, or OCA 25 mg. The primary endpoint was time to first occurrence of prespecified clinical outcomes, including progression to cirrhosis. Secondary endpoints included measures of histologic improvement of the last biopsy using NASH CRN scoring criteria and a 3-pathologist consensus read method.¹

Investigators noted baseline demographics and clinical characteristics were balanced across treatment groups. Efficacy was assessed in the intent-to-treat population, which included 2187 patients. Clinical outcomes occurred in 18.8%, 15.8%, and 14.7% of patients treated with placebo, OCA 10 mg, and OCA 25 mg, respectively. Compared to placebo, the hazard ratio was 0.814 for OCA 10 mg and 0.772 for OCA 25 mg, which investigators noted was driven by fewer patients receiving OCA progressing to cirrhosis.¹

Additionally, more patients receiving OCA had fibrosis improvement compared to placebo, and improvement in fibrosis by ≥1 stage was achieved in 27.0%, 37.1%, and 39.3% of patients treated with placebo, OCA 10 mg, and OCA 25 mg, respectively. Investigators observed worsening of fibrosis by ≥1 stage in 23.5% of patients receiving placebo, 19.3% of patients receiving OCA 10 mg, and 18.5% of patients receiving OCA 25 mg.¹

Treatment-emergent adverse events, serious treatment-emergent adverse events, and deaths were similar across groups. Investigators noted that, consistent with the month 18 analysis, pruritus and gallbladder- and gallstone-related treatment-emergent adverse events occurred more frequently with OCA 25 mg than with placebo or OCA 10 mg.¹

References:

1. ^{Sanyal AJ, Loomba R, Anstee QM, et al. FINAL RESULTS FROM THE PHASE 3 REGENERATE TRIAL EVALUATING THE EFFECTS OF OBETICHOLIC ACID IN PATIENTS WITH PRE-CIRRHOTIC FIBROSIS DUE TO NONALCOHOLIC STEATOHEPATITIS. Abstract presented at Digestive Disease Week (DDW) 2024 Annual Meeting. Washington, DC. May 18-21, 2024.}
2. ^{Campbell, P. FDA Committee Votes Against Risk-Benefit Profile of OCA 25 mg for NASH. HCPLive. May 19, 2023. Accessed May 21, 2024. https://www.hcplive.com/view/fda-committee-votes-against-risk-benefit-profile-of-oca-25-mg-for-nash}
3. ^{Intercept Pharmaceuticals. Intercept Receives Complete Response Letter from FDA for Obeticholic Acid as a Treatment for Pre-Cirrhotic Fibrosis due to NASH. June 22, 2023. Accessed May 21, 2024. https://www.interceptpharma.com/about-us/news/?id=2693358}